2-44320435-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000341.4(SLC3A1):ā€‹c.1854G>Cā€‹(p.Met618Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in Lovd.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.000047 ( 0 hom. )

Consequence

SLC3A1
NM_000341.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.144
Variant links:
Genes affected
SLC3A1 (HGNC:11025): (solute carrier family 3 member 1) This gene encodes a type II membrane glycoprotein which is one of the components of the renal amino acid transporter which transports neutral and basic amino acids in the renal tubule and intestinal tract. Mutations and deletions in this gene are associated with cystinuria. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]
PREPL (HGNC:30228): (prolyl endopeptidase like) The protein encoded by this gene belongs to the prolyl oligopeptidase subfamily of serine peptidases. Mutations in this gene have been associated with hypotonia-cystinuria syndrome, also known as the 2p21 deletion syndrome. Several alternatively spliced transcript variants encoding either the same or different isoforms have been described for this gene.[provided by RefSeq, Jan 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.07801309).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC3A1NM_000341.4 linkc.1854G>C p.Met618Ile missense_variant Exon 10 of 10 ENST00000260649.11 NP_000332.2 Q07837-1A0A0S2Z4E1
PREPLNM_001171613.2 linkc.*921C>G 3_prime_UTR_variant Exon 14 of 14 ENST00000409411.6 NP_001165084.1 Q4J6C6-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC3A1ENST00000260649.11 linkc.1854G>C p.Met618Ile missense_variant Exon 10 of 10 1 NM_000341.4 ENSP00000260649.6 Q07837-1
PREPLENST00000409411 linkc.*921C>G 3_prime_UTR_variant Exon 14 of 14 1 NM_001171613.2 ENSP00000387095.2 Q4J6C6-4

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152026
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000401
AC:
10
AN:
249352
Hom.:
0
AF XY:
0.0000445
AC XY:
6
AN XY:
134918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000626
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000472
AC:
69
AN:
1461752
Hom.:
0
Cov.:
50
AF XY:
0.0000468
AC XY:
34
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000576
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152026
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74232
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cystinuria Uncertain:1
Jan 16, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
3.0
DANN
Benign
0.63
DEOGEN2
Benign
0.18
T;.;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.42
T;T;T
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.078
T;T;T
MetaSVM
Uncertain
0.29
D
MutationAssessor
Benign
0.77
N;.;.
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.38
N;N;N
REVEL
Benign
0.15
Sift
Benign
0.34
T;T;T
Sift4G
Benign
0.35
T;T;T
Polyphen
0.0010
B;.;.
Vest4
0.042
MutPred
0.15
Loss of methylation at R619 (P = 0.0934);.;.;
MVP
0.74
MPC
0.0062
ClinPred
0.014
T
GERP RS
-1.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.097
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs698761; hg19: chr2-44547574; API